ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.5182G>A (p.Asp1728Asn)

gnomAD frequency: 0.00023  dbSNP: rs763880032
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183107 SCV000235517 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The D1729N variant of uncertain significance has not been published as pathogenic or benign to our knowledge. Thisvariant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al.,2012; Exome Variant Server). In addition, D1729N is a semi-conservative amino acid substitution, which mayimpact secondary protein structure as these residues differ in some properties. This substitution also occurs at aposition that is conserved across species, and in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nevertheless, D1729N is classified as a variant of uncertain significance by another clinicallaboratory in ClinVar (ClinVar SCV000545045.1; Landrum et al., 2016).Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000183107 SCV000545045 uncertain significance not provided 2023-09-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1729 of the SCN5A protein (p.Asp1729Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 201531). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs763880032, gnomAD 0.008%).
Color Diagnostics, LLC DBA Color Health RCV001842926 SCV000904900 uncertain significance Cardiac arrhythmia 2023-04-07 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 1729 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002336462 SCV002641474 uncertain significance Cardiovascular phenotype 2024-03-06 criteria provided, single submitter clinical testing The p.D1729N variant (also known as c.5185G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5185. The aspartic acid at codon 1729 is replaced by asparagine, an amino acid with highly similar properties, and is located in the DIV S5-S6 transmembrane spanning region. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002492817 SCV002789650 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2022-02-02 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001842926 SCV004825369 uncertain significance Cardiac arrhythmia 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 1729 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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